This application is a 371 of PCT/CN99/00196 Nov. 19, 1999.
This invention relates to a series of new agarofuran derivatives, their preparation and pharmaceutical composition containing the same as well as pharmaceutical use thereof, particularly for the treatment of anxiety and/or depression.
Anxiety is a disease of human central nervous system (CNS) and its incidence is increasing in pace with the increasing competition of the society.
Anxiolytics were reported to be best sales among the CNS medication including benzadiazepine compounds (diazepam etc.), buspirone and fluoxetine. But,some of the side effects and defects have been observed such as resistance, addiction, relapse dr slow effect. So it is necessary to develop new anti-anxiety drugs which have better curative effect and lower unwanted effects.
Agarofuran compounds are contained in Aquillaria agallocha Roxb in which 9 compounds as follows have been reported in the following publications. 
Tetrahedron 1963, 19, 1079 (M. L. Maheshwari); Tetrahedron 1963, 19, 1519 (M. L. Mheshwari); Tetrahedron 1965, 21, 115 (K. R. Varma); Phytochemistry 1984, 23, 2068 (K. Yoneda); Phytochemistry 1984, 23, 2066 (T. Nakamish); Acta Pharmaceutica Sinica 1986, 21, 516 (J-S, Yang); Acta Pharmaceutica Sinica 1989, 24,.264 (J-S, Yang); J. Am Chem. Soc. 1967, 89, 5665(H. C. Barret); J. Org. Chem. 1968, 33, 435 (J. A. Marshall); Tetrahedron, 1968, 24, 4917 (C. H. Heathcock); Can. J. Chem. 1968, 46, 2817 (A. Asselin); J. Org. Chem. 1979, 44, 546(G. Buchi); Chinese Chem. Lett. 1991, 2, 425(Q. Liu); Chinese Chem. Lett. 1992, 3, 495 (Q. Liu); J. Org. Chem. 1982, 47, 3254 (J. W. Huffman). All of the reports above were only concerned with chemistry of the compounds without teaching or mentioning their bioactivity.
The aim of this invention is to find new anxiolytics, which have better efficacy and lower toxicity.
This invention has made discovery of the following new agarofuran compounds, which have therapeutic effects, particularly anti-anxiety effect, with better safety profile.
The first aspect of the invention relates to compounds of the formula (I) and/or stereoisomers thereof 
wherein
a double bond may or may not exist in A ring at position 2-3 or position 3-4; R1, R2 and R3 are respectively at position 2, 3 or 4. R1 and R2 or R2 and R3 are independently at position 2, 3, or 4.
R1 is H, C2-12 straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be substituted with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substitutent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring containing at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R2 is H, oxo, hydroxyl, C1-C12 straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds, the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which ary is unsubstituted or substituted by one or more substituent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; In the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R3 is H, oxo, hydroxyl or halogen.
Provided that, R1, R2, and R3 are not H at the same time.
According to the present invention, the compounds of the formula (I) exhibit prominent anti-anxiety activity which is characterized by its fast action, longer duration, lower dosage, higher safety coefficient and accompanied by anti-depression effect.
The another aspect of the invention provides a pharmaceutical composition comprising as active ingredient at least one compound of formula (I) or stereoisomer thereof and a pharmaceutical carrier or excipient.
The invention further includes the compound of formula (I) or composition containing it useful for prevention or treatment of anxiety and/or depression.
The invention further provides a method for prevention and/or treatment of anxietyxe2x80x94depression, which comprises administrating at least one compound of formula (I) or composition containing the same to host who needs prevention and/or treatment.
According to the present invention, compounds of formula (I) have exhibited anti-anxiety activity in elevated plus maze test and social interaction test on rat which are typical pharmacological model for axiolytics. Furthermore, a compound of formula (I) showed antidepressant activity in forced swimming test of mice which is typical pharmacological model for anti-depressants.
Specifically, the invention relates to agarofuran derivatives of formula (I) and their stereoisomers, 
wherein
a double bond may or may not exist in A ring at position 2-3 or position 3-4; R1, R2 and R3 are respectively at position 2, 3 or 4. R1 and R2 or R2 and R3 are independently at position 2, 3, or 4.
R1 is H, C2-12 straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be substituted with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substitutent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring containing at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R2 is H, oxo, hydroxyl, C1-C12 straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds, the above defined alkyl may be unsubstituted or substituted by one or more substituents such as hydroxyl or carbonyl, said alkyl may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which ary is unsubstituted or substituted by one or more substituent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; In the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R3 is H, oxo, hydroxyl or halogen.
Provided that, R1, R2, and R3 are not H at the same time.
According to the present invention, a preferred group of compounds of formula (I) is indicated as formula (Ia), wherein there is a double bond in A ring at position 2-3; R1 is defined as above and at position 2; R2 and R3 are H, provided that R1 is not H. 
According to the present invention a preferred group of compound of formula (I) is indicated as formula (Ib), wherein there is no double bond in A ring; R1 and R2 are both at position 2, wherein R1 is as previously defined; R2 is H or OH, R3 is H, provided that R1 is not H. 
According to the present invention, a preferred group of compounds of formula (I) is indieated as formula (Ic), wherein there is no double bond in A ring; R1 is at position 2; R2 and R3 are both at position 3 in A ring; R1, R2 and R3 are as previously defined, provided that R1 and R2 are not hydrogen at the same time. 
According to the present invention, a preferred group of compounds of formula (I) is indicated as formula (Id) in which there is a double bond at position 3-4 in A ring; wherein R2 is at position 2, R2 is a C1-12 straight or branched alkyl chain, saturated or unsaturated, for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by one or more substituent such as substituents such as hydroxyl or carbonyl, it may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substituent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl
R1 and R3 are H. 
According to the present invention, a preferred group of compounds of formula (I) is indicated as formula (Ie) in which there is a double bond at position 2-3 in A ring and R2 is at position 3 ; wherein R2 is a C2-12 straight or branched alkyl;, chain, saturated or unsaturated; for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by hydroxyl or carbonyl; it may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or ore substitutent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
R1 and R3 are H. 
A particularly preferred group of compounds of formula (1) is as follows:
(1R,6S,9R)6,10,10-Trimethyl-2-propyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-butyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-pentyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-hexyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-isopentyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-benzyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-(4-fluorobenzyl)-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,6S,9R)6,10,10-Trimethyl-2-(3-hydroxypropyl)-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1S,2R,6S,9R)6,10,10-Trimethyl-2-butyl-11-oxatricyclo[7.2.1.01,6]dodecane;
(1S,2S,6S,9R)6,10,10-Trimethyl-2-butyl-11-oxatricyclo[7.2.1.01,6]dodecane;
(1R,2S,6S,9R)6,10,10-Trimethyl-2-butyl-2-hydroxy-11-oxatricyclo[7.2.1.01,6]dodecane;
(1R,2R,6S,9R)6,10,10-Trimethyl-2-butyl-11-oxatricyclo[7.2.1.01,6]dodecane;
(1R,6S,9R)6,10,10-Trimethyl-2-butylidene-11-oxatricyclo[7.2.1.01,6]dodecane;
(1S,2S,6S,9R)6,10,10-Trimethyl-2-(3-hydroxypropyl)-11-oxatricyclo[7.2.1.01,6]dodecane;
(1S,2R,6S,9R)6,10,10-Trimethyl-2-butyl-11-oxatricyclo[7.2.1.01,6]dodecane;
(1S,2S,3S,6R,9R)6,10,10-Trimethyl-2-butyl-3-hydroxy-11-oxatricyclo[7.2.1.01,6]dodecane;
(1S,2R,6R,9R)6,10,10-Trimethyl-2-butyl-11-oxatricyclo[7.2.1.01,6]dodec-3-one;
(1S,3S,6R,9R)6,10,10-Trimethyl-3-butyl-3-hydroxy-11-oxatricyclo[7.2.1.01,6]dodecane;
(1R,1xe2x80x2R,6S,9R)6,10,10-Trimethyl-2-(1-hydroxybutyl)-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
(1R,1xe2x80x2S,6S,9R)6,10,10-Trimethyl-2-(1-hydroxybutyl)-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
2-Butyryl(1R,6S,9R)6,10,10-Trimethyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene;
Methyl(1R,6S,9R)6,10,10-Trimethyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene-2-ethyl ketone;
(1S,6R,9R)6,10,10-Trimethyl-3-butyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene; 
In the present invention, compounds of formula (Ia)-(Ie) may be prepared by reaction scheme I-V 
Wherein R1 is as previously defined, X is halogen. 
Where compound of formula (Ib-1) is a specific kind of formula (Ib) wherein R1 is as previously defined; R2 is xcex2-OH, or 
Where compound of formula (Ib-2) is a specific kind of formula (Ib) wherein R1 is as previously defined, R2 is xcex1-OH, or 
Where compound of formula (Ib-3) is a specific kind of formula (Ib) wherein R1 is as previously defined and at xcex1-position, R2 is H, or 
Where compound of formula (Ib-4) is a specific kind of formula (Ib) wherein R1 is as previously defined and at xcex2-position, R2 is H. 
Where compound of formula (Ic-1) is a specific kind of formula (Ic) wherein R1 is as previously defined, R2 is H, and R3 is OH, or 
Where compound of formula (Ic-2) is a specific kind of formula (Ic) wherein R1 is as previously defined, R2 and R3 are oxygen, or 
Where compound of formula (Ic-3) is a specific kind of formula (Ic) wherein R2 is as previously defined, R1 is H, and R3 is OH, or 
Where compound of formula (Ic-4) is a specific kind of formula (Ic) wherein R1 and R2 are H, R3 is halogen. 
where R2 is a C1-C12 straight or branched alkyl chain, saturated or unsaturated; for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by hydroxyl or carbonyl; it may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substitutent such as straight or branched C1-C4 alkyl, alkoxyl, halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl. R2 is at xcex1 position in formula (Id-1) and at xcex2-position in formula (Id-2). 
Wherein R2 is a C1-12 straight or branched alkyl chain, saturated or unsaturated; for unsaturated chain, it may include 1-3 double bonds; the above defined alkyl may be unsubstituted or substituted by hydroxyl or carbonyl; it may also be attached with cycloalkyl, heterocycle containing one or more heteroatoms or aryl group in which aryl is unsubstituted or substituted by one or more substitutent such as straight or branched C1-C4 alkyl, alkoxyl or groups such as halogen, trihalomethyl, amino, hydroxyl, nitro or N,N-dialkylamino; in the above definition, heterocycle is saturated or unsaturated mono-ring or poly-ring having at least one heteroatom selected from oxygen, sulfur or nitrogen; aryl includes phenyl and naphthyl; the substituent may be at any possible position of the alkyl.
In Scheme 1, (6R/S,9R)6-methyl-9-(1-methylvinyl)-bicyclo[4.4.0]deca-1-ene-3-one (formula 1) reacts with alkyl halide R1X (R1 is as previously defined but not H, X is halogen) in the presence of alkaline medium in organic solvent, such as benzene, t-butanol of any other organic solvent that does not interfere with the reaction, to form (6R/S,9R)2-R1-6-methyl-9-(1-methylvinyl)bicyclo[4.4.0]dec-1-ene-3-one (formula 2). The reaction is generally conducted at reflux temperature of the solvent used and the preferable alkaline reagents are metallic alkoxide or hydride such as sodium hydride and potassium t-butoxide. Reaction of compound of formula (2) with organic peracid, preferably meta-chloro-perbenzoic acid, to form (6R/S,9R)2-R1-6-methyl-9-(1-methyl-epoxyethyl)bicyclo[4.4.0]-dec-1-ene-3-one (3). The reaction are conducted generally in organic solvents such as methylene chloride, chloroform, diethylether or any other solvent that does not interfere with the reaction, and at room temperature or lower temperature. Reduction of compound (3) with reducing agents such as metal hydride complex, preferably lithium aluminum hydride, to form compound of formula (4). The reactions are generally conducted at room temperature or lower temperature in organic solvent such as diethylether, tetrahydrofuran, methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction. Compound (4) is converted to compound of formula (Ia) by treatment with acid, preferably inorganic acid, such as hydrochloric acid, sulfuric acid, or phosphoric acid and the reaction is generally conducted in solvents such as water, methanol, ethanol, diethylether, benzene, toluene, methylene chloride, chloroform, ethylacetate, tetrahydrofuran or a mixture thereof, preferably benzene-water, diethylether-water system at room temperature or lower temperature.
In Scheme II, compound of formula (Ia) is reacted with organic peracid, preferably meta-chloroperbenzoic acid, to form compound of formula (5) in organic solvent such as diethylether, methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or lower temperature. The compound (5) thus formed is reduced by metal hydride complex or borane, such as LiAlH4/Lewis acid, preferably LiAlH4 or LiAlH4/AlCl3, to form compound of formula (Ib-1). The reaction is conducted in organic solvent such as diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. (1R,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.0]dodecean-2-one (formula 6) reacts with organometallic reagent such as Grignard reagent or organolithium reagent to form compound of formula (Ib-2). The reaction can be conducted in organic solvent such as diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath or ice-salt mixture. Compound of formula (Ib-1) can be converted to compound of formula (7) when treated with thionyl chloride, phosphorus oxychloride, phosphorus pentoxide in 44 pyridine, or triethylamine at room temperature, or cooled with ice bath or ice-salt mixture. Catalytic hydrogenation of (7) to form compound of formula (Ib-3). The hydrogenation is catalyzed by generally used catalysts such as platinum oxide, Raney Ni, palladium on carbon, or rhodium on carbon etc. in organic solvent such as ethanol, methanol, acetic acid or any other solvent that does not. interfere with the reaction at room temperature. Similarly, catalytic hydrogenation of compound of formula (Ia) forms compound of formula (Ib-4) and the reaction is catalyzed by generally used catalysts such as platinum oxide, Raney Ni, palladium on carbon, or rhodium on carbon etc. in organic solvent such as ethanol, methanol, acetic acid or any other solvent that does not interfere with the reaction at room temperature.
In Scheme III, compound of formula (5) is reduced by metallic hydride complex, preferably LiAlH4, to form compound of formula (Ic-1) in organic solvent such as diethylether, tetrahydrofuran, 1,2-dimethoxyethane, or any other solvent that does not interfere with the reaction at room temperature. Oxidation of compound of formula (Ic-1) by CrO3/pyridine, pyridinum chlorochromate (PCC) or Jones reagent, preferably PCC, produces compound of formula (Ic-2) and the reaction is generally conducted in organic solvent such as methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or heated. (1S,6S,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene (formula 8) is oxidized by organic peracid, preferably meta-chloroperbenzoic acid, to form (1S,2S,6R,9R)6,10,10-trimethyl-2,3-epoxy-11-oxatricyclo[7.2.1.01,6]dodecane (formula 9) and the reaction is conducted in organic solvent such as diethylether, methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or cooled. The thus produced compound (9) is reduced by metallic hydride complex, preferably LiAlH4 to form (1S,3S,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodecan-3-one (formula 10) and the reaction is conducted in organic solvent such as diethylether, tetrahydrofuran, 1,2-dimethoxyethane or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Compound of formula (10) is oxidized by CrO3/pyridine, PCC, or Jones reagent, preferably PCC to form (1S,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodecan-3-one (formula 11 ) and the reaction is conducted in organic solvent such as methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or heated. Compound (11) is reacted with organometallic reagent such as Grignard reagent or organolithium reagent to form compound of formula (Ic-3) and the reaction is conducted in organic solvent such as diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Compound of formula (10) react with phosphorous trihalide in the presence of triphenylphosphine to form (1S,3R,6R,9R)6,10,10-trimethyl-3-halo-11-oxatricyclo[7.2.1.01,6]dodecane and the reaction is conducted in anhydrous diethylether and cooled with ice bath or ice-salt mixture.
In Scheme IV, compound (9) reacts with Grignard reagent to form compound of formula (12) and the reaction is usually carried out in diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Treatment of compound of formula (12) with pyridine/thionyl chloride to eliminate a molecule of water produces compounds of formula of (Id-1) and (Id-2) and the reaction is carried out at room temperature or cooled with ice bath or ice-salt mixture.
Compound of formula (13) may be prepared following the similar method for preparation of compound of formula (Ic-1).
In Scheme V, treatment of (6R/S,9R)-6-methyl-9-(1-methylvinyl)-bicyclo[4,4,0]dec-1-ene-3-one (1) with mixture of sulfuric acid and formic acid at room temperature produces (6R/S,9R)-6methyl-9-(1-hydroxyisopropyl)-bicyclo[4.4.0]-dec-1-ene-3-one (14). Compound (14) reacts with organometallic reagent such Grignard reagent or organolithium reagent to form compound of formula (15) and the reaction is conducted in diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath or ice-salt mixture. Cyclization of compound of formula (15) to form compound of formula (Ie) is carried out in acidic medium, optionally with inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid in any solvent that does not interfere with the reaction such as water, methanol, ethanol, diethylether, benzene, toluene, methylene chloride, chloroform, ethylacetate, tetrahydrofuran, or a mixture thereof, particularly benzene-water, diethylether-water mixture. The reaction temperature is usually room temperature or lower.
In this invention, the term xe2x80x9calkylxe2x80x9d, unless otherwise indicated, refers to straight or branched carbon chain with 2 to 12 carbon atoms, such as ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, 1-methybutyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, or decyl and sail alkyl may be unsubstituted or substituted by hydroxyl or carbonyl on the chain.
In this invention, the term xe2x80x9chalogenxe2x80x9d refers to as fluoro, chloro, bromo, or iodo.
The term xe2x80x9cunsaturated alkylxe2x80x9d, unless otherwise indicated, refers to straight or branched carbon chains which contain 2 to 12 carbon atoms and 1 to 3 double bond in it, for example vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl. Said unsaturated alkyl may be unstubstituted or substituted by hydroxyl or oxo. Compound of formula (I) may contain chiral centers of S or R configuration., therefore may have stereoisomers. The invention includes all the possible enantiomers and diastereomers, both mixtures and separated individual isomers. The mixture of two enantiomers, that is levo and dextro, may exist in different ratio. If there is cis, trans isomer, the invention includes the cis, trans isomers or the mixture thereof. The individual stereoisomer may be prepared by conventional resolution method or by stereoselective synthesis. If there is active H, the invention may also include tautomers.
Compound of formula (I) and their stereoisomers have showed activity on experimental anti-anxiety tests, therefore may be used as anxiolytic for living creature, particularly for mammals, especially for human being.
This invention also provides pharmaceutical composition comprising at least one active compound of formula (I) and/or its stereoisomer, or a pharmaceutically acceptable salt thereof as well as conventional pharmaceutically excipient or adjuvant. The composition 0.1%xcx9c90% by weight a compound of formula (I) or a pharmaceutically salt thereof and is prepared by the known method in this field. For this purpose, it may combine compound of formula (I) with one or more solid of liquid excipient and/or adjuvant, to make proper administration or dosage form for use in medicine or veterinary medicine.
The compounds represented by the general formula (1) are administrated alone or in the form of a pharmaceutical composition containing the same, administration route may be intestinal or parenteral, such as oral, intramuscular, subcutaneous, transdermally, intransally, intraperitoneally, rectally, topically, and the like. Said pharmaceutical preparations are formulated. by using usually used diluents such as fillers, bulking fillers, binders, wetting agents, disintegrants, surface active agents, lubricants; or excipients. The pharmaceutical preparations can be selected from various administration forms in accordance with the therapeutic purposes. As to typical administration forms, there can be exemplified tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (liquids, suspensions, etc.), slowly releasing preparation, preparation form controlling release and the like. For the purpose of shaping the administration unit form into the tables, various carriers which are well-known in this field can be widely used. As to the examples of carriers, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystal-line cellulose, aluminum silicate and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrants such as dry starch, sudium alginate, agar-agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose and the like; disintegration inhibitors such as white sugar, stearin, cacao butter, hydrogenated oils and the like; absorption accelerators such as quaternary ammonium salts, sodium laurylsulfate and the like; wetting agents such as glycerin, starch and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like; lubricants such as refined talc, strearates, boric acid powders, polyethylene glycols and the like can be mentioned. The tablets preparations can be further shaped into tablets coated with usual tablet coating, for example sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coating, tablets coated with film coating, or double layer tablets and multiple layer tablets. For the purpose of shaping the administration unit into pills, various carriers which are well-known in this field can be widely used. As to the examples of carriers, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and the like; binders such as powdered acacia, powdered tragacanth, gelatin, ethanol and the like can be exemplified. For the purpose or shaping the administration unit into suppositories, various carriers which are well-known in this field can be widely used. As to the examples of carries, polyethylene glycols, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthesized glycerides and the like can be mentioned. For the purpose of shaping the administration unit form into capsules, the compounds of formula (I) as the effective ingredient is mixed with the above-mentioned various carriers and the mixture thus obtained is placed into rigid gelatin capsules or soft capsules. For the purpose of shaping the administration unit into injection preparations, liquid preparations, emulsion preparations and suspension preparations are sterilized, further these preparations are preferably isotonic to the blood, and the all diluents which are conventionally used in this field can also be used for example, water, ethyl alcohol, macrogols, propylene glycol, ethyoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylenesorbitan fatty acid esters can be used. Additionally, for the purpose to prepare isotonic injection solutions, an adequate amount of sodium chloride, glucose or glycerin may be added to the injection preparations, further, usual dissolving additives, buffering agents, local anesthetics and the like may be added. Moreover, if necessary, coloring agents, preservatives, spices, flavors, sweetening agents and others may be added to the pharmaceutical preparations.
Dose of pharmaceutical preparation of the present invention is suitably selected depend on the usage, age of the patient, distinguish of sex and other conditions, and degree of the symptom, and generally the daily amount of effective compound of formula (I) may be about 0.001 to 100 mg/about 75 kg of the body weight per day, preferably about 0.01 to 20 mg. The above preparation may be administrated in single dose or to be divided into several dose such two, three or four dose.